This proposed research is directed toward the site-specific delivery of oxidants to malaria-infected erythrocytes. As malaria parasites and their host erythrocytes are highly susceptible to oxidant stress, additional oxidant damage to the parasite/host erythrocyte system may lead to an interruption of the parasite life cycle. Since chloroquine and related quinoline are selectively concentrated in the digestive vacuoles of the erythrocytic form of the malarial parasite, and since infected erythrocytes possess a specific uptake mechanism for L-isoleucine, nine peroxide, oxazirane and "redox" analogy of chloroquine, and six peroxide derivatives of L-isoleucine are proposed as site-specific oxidant antimalarial. The proposed syntheses of the target quinoline oxidants rely on two key transformations. The first is a Mannish type condensation between secondary amines, formaldehyde, and hydroperoxides; and the second is the peracid oxidation of imines to oxaranes. The L- isoleucine peroxides will be synthesized using proxide chemistry adapted to amino acids. The proposed site-specific oxidants will be evaluated for antimalarial activity against in vitro P falciparum, and in vivo P. bergh in collaboration with Dr. John Eaton at the University of Minnesota and the Walter Reed Army Institute of Research. If an increase in antimalarial activity or potency is observed consistent with the hypothesis states above, then experiments with Dr. Eaton will be conducted to assess their specificity for the infected erythrocyte/parasite system, and to determine mechanism (s) of oxidant damage. Finally, incorporation of oxidant functionality into drugs effective against other oxidant sensitive protozoa may result in superior agents, and extension of the concept of site-specific delivery of oxidants.